Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR

// Susana Llerena 1, 2, * , Nuria Garcia-Diaz 3, 4, * , Soraya Curiel-Olmo 3 , Antonio Agraz-Doblas 4, 5 , Agustin Garcia-Blanco 1, 2 , Helena Pisonero 2, 4 , Maria Varela 6 , Miguel Santibanez 7 , Carmen Almaraz 3 , Laura Cereceda 3 , Nerea Martinez 3 , Maria Teresa Arias-Loste 1, 2 , Angela Puente 1, 2 , Luis Martin-Ramos 1, 2 , Carlos Rodriguez de Lope 1, 2 , Federico Castillo-Suescun 8 , Carmen Cagigas-Fernandez 8 , Pablo Isidro 9 , Carlos Lopez-Lopez 10 , Marcos Lopez-Hoyos 11 , Javier Llorca 12, 13 , Jesus Aguero 14 , Benedicto Crespo-Facorro 15, 16 , Ignacio Varela 4 , Miguel Angel Piris 17, ** , Javier Crespo 1, 2, ** and Jose Pedro Vaque 2, 4, ** 1 Gastroenterology and Hepatology Unit, Hospital Universitario Marques de Valdecilla, Santander, Spain 2 Infection, Immunity and Digestive Pathology Group, IDIVAL, Santander, Spain 3 Translational Hematopathology Group, IDIVAL, Instituto de Investigacion Marques de Valdecilla, Santander, Spain 4 Departamento de Biologia Molecular, Universidad de Cantabria (UC-IBBTEC), Santander, Spain 5 Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain 6 Digestive Service, Hepatology Unit, Hospital Universitario Central de Asturias, Oviedo, Spain 7 Universidad de Cantabria-IDIVAL, Santander, Spain 8 General and Digestive Tract Surgery Service, Hospital Universitario Marques de Valdecilla, Santander, Spain 9 Biobanco-Hospital Universitario Central de Asturias, Oviedo, Spain 10 Oncology Service, Hospital Universitario Marques de Valdecilla, Santander, Spain 11 Immunology Service, Hospital Universitario Marques de Valdecilla, Santander, Spain 12 Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, Santander, Spain 13 CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain 14 Microbiology Service, University Hospital Marques de Valdecilla-IDIVAL, Santander, Spain 15 Department of Psychiatry, Marques de Valdecilla University Hospital-IDIVAL, Santander, Spain 16 CIBERSAM, Centro de Investigacion Biomedica en Red Salud Mental, Madrid, Spain 17 Department of Pathology, Fundacion Jimenez Diaz, Madrid, Spain * These authors have contributed equally to this work ** Senior author Correspondence to: Jose Pedro Vaque, email: vaquej@unican.es Keywords: hepatocellular carcinoma; mutations; sorafenib; targeted therapy; AKT/mTOR Received: January 16, 2018     Accepted: June 22, 2018     Published: July 20, 2018 ABSTRACT Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.